Publications by authors named "Kuan Hu"

72 Publications

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

The novel roles of virus infection-associated gene CDKN1A in chemoresistance and immune infiltration of glioblastoma.

Aging (Albany NY) 2021 Feb 17;13(5):6662-6680. Epub 2021 Feb 17.

Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

Chemoresistance is a common limitation for successful treatment of glioblastoma multiforme (GBM). Recently, virus infections have been demonstrated to be associated with tumorigenesis and chemoresistance in tumors. However, the role of infection-related genes in GBM haven't been clearly demonstrated. Here, we explored the roles and mechanisms of human T-lymphotropic virus type-1 (HTLV-1) infections in tumorigenesis and chemoresistance in GBM. Four candidate genes, CDKN1A, MSX1, MYC and CHEK2, were identified to be the codifferentially expressed genes between three temozolomide (TMZ) chemotherapy datasets and one HTLV-1 infection gene set. Next, comprehensive bioinformatics data from several databases indicated that only CDKN1A was significantly upregulated in both GBM tissues and cells and showed the greatest prognostic value in GBM patients. Clinical data identified the correlations between CDKN1A expression and clinicopathological parameters of GBM patients. Moreover, CDKN1A was found to be involved in AKT-mediated TMZ resistance of glioma cells. In addition, KEGG analysis of CDKN1A-associated coexpression genes showed that CDKN1A was potentially involved in complement and coagulation cascades pathways in GBM. Finally, TISIDB database was used to investigate the role of CDKN1A in tumor-immune system interactions in GBM. These findings enhanced our understanding of the roles of CDKN1A in tumorigenesis and therapy response in GBM.
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http://dx.doi.org/10.18632/aging.202519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993694PMC
February 2021

Prognostic Value of PLXND1 and TGF-β1 Coexpression and Its Correlation With Immune Infiltrates in Hepatocellular Carcinoma.

Front Oncol 2020 8;10:604131. Epub 2021 Jan 8.

Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with no curative treatments. Plexin D1 (PLXND1) is a cellular receptor whose functions have been explored in several human cancers; however, the critical roles of PLXND1 in HCC have rarely been probed. Therefore, the present study attempted to elucidate the expression pattern, prognostic significance, and potential roles of PLXND1 in HCC. We found that PLXND1 expression in HCC tissues was significantly higher compared with normal liver tissue from Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB) databases. This result was further validated by immunohistochemistry staining (IHC) using tissue microarrays, which contained 216 HCC cases collected from our hospital. Additionally, PLXND1 expression showed a significant correlation with several clinical characteristics, including tumor grade and tumor hemorrhage (TH). Moreover, TISIDB and GEPIA databases were used to investigate the roles of PLXND1 in tumor-immune system interactions in HCC. As an immunoinhibitor, transforming growth factor-beta (TGF-β1) displayed the greatest correlations with PLXND1 in HCC. Finally, Kaplan-Meier curves and Cox analysis were conducted to further examine the potential clinical value of PLXND1 in HCC. We described a subclassification of HCC based on PLXND1 and TGF-β1 expression, which could be used to predict clinical outcomes and patient prognosis. Taken together, the results of this study indicate that PLXND1 might be a promising prognostic biomarker and potential therapeutic target in HCC.
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http://dx.doi.org/10.3389/fonc.2020.604131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820679PMC
January 2021

Spectrum of Mesenchymal-Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis.

Front Oncol 2020 15;10:560615. Epub 2020 Oct 15.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.

Background: The receptor tyrosine kinase mesenchymal-epithelial transition factor (MET) is frequently altered in cancers and is a common therapeutic target for cancers with MET variants. However, abnormal MET alterations and their associations with patient outcome across different cancer types have not been studied simultaneously. In this study, we try to fill the vacancy in a comprehensive manner and capture the full MET alteration spectrum.

Methods: A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).

Results: MET abnormal expression, alteration frequency, mutation site distribution, and functional impact varied across different cancer types. Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis. Kidney renal papillary cell carcinoma (KIRP) harbored the third highest alteration frequency of MET, which was dominated by mutations. While most mutations were in the Pkinase_Tyr domain, a few were targetable. Pancreatic adenocarcinoma (PAAD) harbors very few alterations, but increased MET expression is associated with poor outcomes. Esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), and ovarian serous cystadenocarcinoma (OV) had similar characteristics: a high frequency of MET CNVs but relatively few MET mutations, and high MET expression associated with poor prognosis.

Conclusion: This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.
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http://dx.doi.org/10.3389/fonc.2020.560615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593712PMC
October 2020

Investigating effects of preoperative inflammatory biomarkers on predicting survival outcomes of intrahepatic cholangiocarcinoma after curative resection.

World J Surg Oncol 2020 Oct 23;18(1):272. Epub 2020 Oct 23.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Introduction: Intrahepatic cholangiocarcinoma (ICC) stands as the second most common malignant tumor in the liver with poor patient prognosis. Increasing evidences have shown that inflammation plays a significant role in tumor progression, angiogenesis, and metastasis. However, the prognosis significance of inflammatory biomarkers on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is poorly recognized.

Methods: ICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII), were investigated.

Results: Receiver operating characteristic (ROC) curves showed no significance in NLR, PLR, and LMR in RFS and OS, while significant results were shown on SII in both RFS (P = 0.035) and OS (P = 0.034) with areas under ROC curve as 0.63 (95%CI 0.52-0.74) and 0.62 (95%CI 0.51-0.72), respectively. Kaplan-Meier curves revealed a statistically significant better survival data in SII-low groups on both RFS (P < 0.001) and OS (P < 0.001). The univariate and multivariate analyses revealed that higher level of SII was independently associated with both poorer RFS time and OS time. However, no significant result was shown on NLR, PLR, or LMR.

Conclusion: SII is an effective prognostic factor for predicting the prognosis of ICC patient undergone curative hepatectomy, while NLR, PLR, and LMR are not associated with clinical outcomes of these patients.
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http://dx.doi.org/10.1186/s12957-020-02053-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585228PMC
October 2020

Smart Titanium Coating Composed of Antibiotic Conjugated Peptides as an Infection-Responsive Antibacterial Agent.

Macromol Biosci 2021 01 13;21(1):e2000194. Epub 2020 Oct 13.

Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.

Antibacterial coating is rapidly emerging as a pivotal strategy for mitigating spread of bacterial pathogens. However, many challenges still need to be overcome in order to develop a smart coating that can achieve on-demand antibacterial effects. In this study, a Staphylococcus aureus (S. aureus) sensitive peptide sequence is designed, and an antibiotic is then conjugated with this tailor-made peptide. The antibiotic-peptide conjugate is then linked to the surface of a titanium implant, where the peptide can be recognized and cleaved by an enzyme secreted by S. aureus. This allows for the release of antibiotics in the presence of S. aureus, thus achieving delivery of an antibacterial specifically when an infection occurs.
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http://dx.doi.org/10.1002/mabi.202000194DOI Listing
January 2021

Synthesis and preliminary studies of C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.

Theranostics 2020 14;10(24):11178-11196. Epub 2020 Sep 14.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.

Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu using positron emission tomography (PET) would allow for quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu. A focused small molecule library of mGlu NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.
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http://dx.doi.org/10.7150/thno.42587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532674PMC
September 2020

Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[C]methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu).

J Med Chem 2020 10 22;63(20):11469-11483. Epub 2020 Sep 22.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Metabotropic glutamate receptor 2 (mGlu) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu, we identified new candidates - that are potent negative allosteric modulators (NAMs) of mGlu. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide (, also named as [C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound was labeled with positron-emitting carbon-11 (C) to obtain [C] in high radiochemical yield and high molar activity by -[C]methylation of the phenol precursor with [C]CHI. autoradiography with [C] showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [C] indicated specific binding of mGlu in the rat brain. Based on the [C] scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892210PMC
October 2020

3-(Cyclopropylmethyl)-7-((4-(4-[C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2.

Bioorg Med Chem Lett 2020 12 15;30(23):127555. Epub 2020 Sep 15.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [C]CMTP ([C]1a) was synthesized by O-[C]methylation of desmethyl precursor 1b with [C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [C]CO) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [C]1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [C]1a was able to cross the blood-brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain.
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http://dx.doi.org/10.1016/j.bmcl.2020.127555DOI Listing
December 2020

Radiotheranostic Agent Cu-cyclam-RAFT-c(-RGDfK-) for Management of Peritoneal Metastasis in Ovarian Cancer.

Clin Cancer Res 2020 Dec 15;26(23):6230-6241. Epub 2020 Sep 15.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Purpose: Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αβ integrin (αβ) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αβ-positive OCPM mouse models, we studied the theranostic potential of an αβ-specific radiopeptide, Cu-cyclam-RAFT-c(-RGDfK-) (Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.

Experimental Design: αβ-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.

Results: Intraperitoneal administration was an efficient route for targeting Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. Cu-RaftRGD-based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2-17.2 mm). Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.

Conclusions: Collectively, these results demonstrate the all-in-one potential of Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αβ- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1205DOI Listing
December 2020

WAVE2 Enhanced Hepatic Stellate Cells Activity in Colorectal Liver Metastases.

Cancer Manag Res 2020 24;12:7671-7680. Epub 2020 Aug 24.

Department of General Surgery Research, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Background: Cancer cell migration, tumor angiogenesis, and activated hepatic stellate cells (a-HSCs) promote the development of colorectal liver metastases (CLM). Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 (WAVE2) has been associated with CLM, although the underlying molecular mechanisms remain unclear.

Methods: In the current study, we evaluated the relationship between WAVE2 and CLM in 103 CLM patients who underwent liver resection. Immunohistochemistry (IHC) staining was performed to determine the association between WAVE2 protein expression and hepatic micro-metastasis in human CLM tissues. WAVE2 knockout was performed in hepatic stellate cells (HSC) to explore the function and signaling pathways of WAVE2 in colorectal cancer progression.

Results: Significantly higher levels of WAVE2 were detected in portal-associated relative to sinusoid-associated micro-metastasis. A strong correlation was identified between WAVE2 levels and microvessel density (MVD) in hepatic metastasis. Similarly, expression of WAVE2 was closely associated with activation of HSCs. Mechanistically, WAVE2 regulated the progression of human CLM acts by regulating the growth factor β (TGF-β) and Hippo pathways via effector yes-associated protein (YAP1).

Conclusion: Overall, our results demonstrated that WAVE2 participates in CLM tumor microenvironment, and can be a potential latent therapeutic target for CLM.
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http://dx.doi.org/10.2147/CMAR.S259125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455535PMC
August 2020

Synthesis and preliminary evaluation of novel C-labeled GluN2B-selective NMDA receptor negative allosteric modulators.

Acta Pharmacol Sin 2021 Mar 13;42(3):491-498. Epub 2020 Jul 13.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [C]31 and [C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [C]CHI in good radiochemical yields (decay-corrected 28% and 32% relative to starting [C]CO, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
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http://dx.doi.org/10.1038/s41401-020-0456-9DOI Listing
March 2021

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[C]methoxyphenethyl)pyridazin-3(2H)-one, a C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Bioorg Med Chem Lett 2020 08 9;30(16):127326. Epub 2020 Jun 9.

Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
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http://dx.doi.org/10.1016/j.bmcl.2020.127326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363051PMC
August 2020

Marriage of black phosphorus and Cu as effective photothermal agents for PET-guided combination cancer therapy.

Nat Commun 2020 06 8;11(1):2778. Epub 2020 Jun 8.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 2638555, Japan.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing Cu, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
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http://dx.doi.org/10.1038/s41467-020-16513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280494PMC
June 2020

PET Imaging of VEGFR with a Novel Cu-Labeled Peptide.

ACS Omega 2020 Apr 8;5(15):8508-8514. Epub 2020 Apr 8.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

Vascular endothelial growth factor receptors (VEGFRs) are well recognized as significant biomarkers of tumor angiogenesis. Herein, we have developed a first-of-its-kind peptide-based VEGFR positron emission tomography (PET) tracer. The novel [Cu]VEGF peptide possessed satisfactory radio-characteristics and showed good specificity for the visualization of VEGFR in various mouse models, in which the tumor-specific radioactivity uptake was highly correlated to the VEGFR expression level. Moreover, the tracer showed high tumor uptake (ca. 5.89 %ID/g at 20 min postinjection in B16F10 mice) and excellent pharmacokinetics, achieving the maximum imaging quality within 1 h after injection. These features convey [Cu]VEGF as a promising, clinically translatable PET tracer for the imaging of tumor angiogenesis.
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http://dx.doi.org/10.1021/acsomega.9b03953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178340PMC
April 2020

Perineural invasion as a prognostic factor for intrahepatic cholangiocarcinoma after curative resection and a potential indication for postoperative chemotherapy: a retrospective cohort study.

BMC Cancer 2020 Mar 30;20(1):270. Epub 2020 Mar 30.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: In the past four decades, the incidence of cholangiocarcinoma, especially intrahepatic cholangiocarcinoma (ICC), has raised rapidly worldwide. Completeness of resection, max size of tumor and etc. are widely recognized as prognostic factors. However, the prognosis significance of perineural invasion (PNI) on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is controversial.

Methods: ICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Patients were grouped by existence of PNI and outcomes were compared between groups. The potential relationship between PNI and postoperative chemotherapy was also investigated.

Results: There was no significant difference in demographic, clinical staging or tumor index between two groups, except positive hepatitis B surface antigen and CA19-9. PNI negative group showed a better prognosis in RFS (P < 0.0001) and OS (P < 0.0001). COX regression analyses showed PNI as an independent risk factor in RFS and OS. ICC with postoperative chemotherapy showed better effects in the whole cohort on both RFS (P = 0.0023) and OS (P = 0.0011). In PNI negative group, postoperative chemotherapy also showed significant benefits on RFS and OS, however not in PNI positive group (P = 0.4920 in RFS and P = 0.8004 in OS).

Conclusion: PNI was an independent risk factor in R0-resected ICC, presenting worse recurrence and survival outcomes. Meanwhile, negative PNI may act as an indication of postoperative chemotherapy.
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http://dx.doi.org/10.1186/s12885-020-06781-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106692PMC
March 2020

HIF1A activates the transcription of lncRNA RAET1K to modulate hypoxia-induced glycolysis in hepatocellular carcinoma cells via miR-100-5p.

Cell Death Dis 2020 03 9;11(3):176. Epub 2020 Mar 9.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.

Hepatocellular carcinoma (HCC) remains the primary cause of cancer-related death. Metabolic change is the major characteristic of cancer. The present study attempted to investigate the regulatory mechanisms of HCC energy metabolism from the perspective of noncoding RNA regulation of HIF1A and LDHA. The expression of miR-100-5p expression was significantly suppressed in HCC tissue samples and HCC cell lines under 1% O-induced hypoxia. miR-100-5p overexpression significantly suppressed hypoxia-induced increases in lactate concentration and glucose uptake. Exposure to 1% O induced HIF1A protein and reduced miR-100-5p expression, while HIF1A silencing dramatically rescued miR-100-5p expression upon 1% O exposure. In addition, 1% O-induced increases in lactate concentration and glucose uptake were also suppressed by HIF1A silencing. Next, by analyzing available data in TCGA, we found that lncRNA RAET1K was correlated with HIF1A and miR-100-5p.LncRNA RAET1K could downregulate the expression of miR-100-5p by acting as a sponge, while HIF1A bound the lncRNA RAET1K promoter region to activate its transcription. LncRNA RAET1K silencing significantly suppressed HCC cell proliferation and invasion and also suppressed hypoxia-induced increases in lactate concentration and glucose uptake, while miR-100-5p inhibition reversed the effects of lncRNA RAET1K silencing on hypoxia-induced glycolysis in HCC cells. Finally, the expression of HIF1A, lncRNA RAET1K, and LDHA was upregulated in HCC tissue specimens; the expression of miR-100-5p was negatively related to HIF1A, lncRNA RAET1K, and LDHA; and HIF1A, lncRNA RAET1K, and LDHA were positively correlated with each other. In conclusion, the HIF1A/lncRNA RAET1K/miR-100-5p axis modulates hypoxia-induced glycolysis in HCC cells and might affect HCC progression.
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http://dx.doi.org/10.1038/s41419-020-2366-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062743PMC
March 2020

Customization of Conductive Elastomer Based on PVA/PEI for Stretchable Sensors.

Small 2020 02 7;16(7):e1904758. Epub 2020 Jan 7.

CAS Center for Excellence in Nanoscience, Beijing Key Laboratory of Micro-nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, 100083, China.

Conductive, stretchable, environmentally-friendly, and strain-sensitive elastomers are attracting immense research interest because of their potential applications in various areas, such as human-machine interfaces, healthcare monitoring, and soft robots. Herein, a binary networked elastomer is reported based on a composite hydrogel of polyvinyl alcohol (PVA) and polyethyleneimine (PEI), which is demonstrated to be ultrastretchable, mechanically robust, biosafe, and antibacterial. The mechanical stretchability and toughness of the hydrogels are optimized by tuning the constituent ratio and water content. The optimal hydrogel (PVA PEI -75) displays an impressive tensile strain as high as 500% with a corresponding tensile stress of 0.6 MPa. Furthermore, the hydrogel elastomer is utilized to fabricate piezoresistive sensors. The as-made strain sensor displays seductive capability to monitor and distinguish multifarious human motions with high accuracy and sensitivity, like facial expressions and vocal signals. Therefore, the elastomer reported in this study holds great potential for sensing applications in the era of the Internet of Things (IoTs).
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http://dx.doi.org/10.1002/smll.201904758DOI Listing
February 2020

Synthesis and evaluation of 6-(C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET.

Bioorg Med Chem Lett 2020 02 17;30(4):126879. Epub 2019 Dec 17.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2019.126879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045276PMC
February 2020

Severe polycystic liver diseases: hepatectomy or waiting for liver transplantation?: Two case reports.

Medicine (Baltimore) 2019 Dec;98(49):e18176

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Introduction: Choice of treatment in patients with symptomatic polycystic liver diseases (PLD) remains controversial. Various surgical procedures aiming at eliminating symptomatic cysts are widely used in mild and advanced PLD patients, but liver transplantation is currently recommended as the only curative treatment especially in severe cases.

Patient Concerns: Case 1: A 51-year-old male was admitted for severe eating disorder and dyspnea for 2 months. He had been diagnosed as PLD, PKD, and hypertension for 9 years, with only antihypertensive drug therapy. No significant family history could be traced.Case 2: A 54-year-old female was admitted to our hospital for ventosity during nearly 5 years. She had been diagnosed as PLD and hypertension for 22 years, for which only aspiration-sclerotherapy therapy was performed for multiple times. Both her mother and sister were diagnosed with PLD previously.

Diagnosis: They were diagnosed as PLD by medical history, family history, and computed tomography scan (multiple cysts dispersively presenting in the liver).

Interventions: The 2 patients underwent hepatectomy with fenestration, and were well recovered with no mortality.

Outcomes: While case 1 only experienced relief of symptoms, case 2 experienced massive growth of hepatic parenchyma, which indicated positive prognosis and showed the possibility to avoid or at least postpone liver transplantation for a long time, considering the lack of liver parenchyma is one of the main reason for urgency of liver transplantation.

Conclusion: Here we described subradical polycystic hepatectomy, a special form of hepatectomy with fenestration modified by us, as a safe and effective treatment to potentially achieve long-term effects in PLD patients.
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http://dx.doi.org/10.1097/MD.0000000000018176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919518PMC
December 2019

Toughening Biosourced Poly(lactic acid) and Poly(3-hydroxybutyrate--4-hydroxybutyrate) Blends by a Renewable Poly(epichlorohydrin--ethylene oxide) Elastomer.

ACS Omega 2019 Nov 13;4(22):19777-19786. Epub 2019 Nov 13.

Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin 300350, China.

A series of sustainable polymer blends from renewable poly(lactic acid) (PLA), poly(3-hydroxybutyrate--4-hydroxybutyrate) (PHB), and poly(epichlorohydrin--ethylene oxide) (ECO) elastomer were fabricated via a melt blending method to gain balanced physical performance. The interplay of the composition, mutual miscibility, and viscosity ratio of the pristine PLA, PHB, and ECO elastomer resulted in diverse phase structures of the ternary blends. An excellent flexibility at an elongation of 270% was achieved for the PLA/PHB/ECO (70/20/10) blend with a core-shell structure. The PLA/PHB/ECO (70/10/20) blend with a phase-separated structure exhibited a high impact strength of 54 KJ/m, which is 25 times over that of the neat PLA. The relationship between the phase structure and physical performance of the blend was analyzed based on the compositions, surface tension, and physical characteristics of the neat components. Combining the compatibilization of the PHB phase and ECO elastomer toughening played a crucial role in enhancing the mechanical properties of the blends.
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http://dx.doi.org/10.1021/acsomega.9b02639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882108PMC
November 2019

Design, Synthesis, and Evaluation of F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes.

J Med Chem 2019 10 26;62(19):8866-8872. Epub 2019 Sep 26.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School , Boston , Massachusetts 02114 , United States.

Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound (identified from a therapeutic agent) was advanced for F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel F-labeled MAGL PET probes.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875603PMC
October 2019

I-IITM and At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1.

J Nucl Med 2020 02 26;61(2):242-248. Epub 2019 Aug 26.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan

Targeted radionuclide therapy (TRT) targeting oncoproteins facilitates the delivery of therapeutic radionuclides to tumor tissues with high precision. Herein, we developed 2 new radiopharmaceuticals, 4-I-iodo- and 4-At-astato--[4-(6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]--methylbenzamide (I-IITM and At-AITM), targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) in melanomas for TRT studies. I-IITM and At-AITM were synthesized by reacting a stannyl precursor with I-NaI and At in the presence of an oxidizing agent. The therapeutic efficacy and safety of the 2 radiopharmaceuticals were investigated using mGluR1-expressing B16F10 melanoma cells and melanoma-bearing mice. I-IITM and At-AITM were obtained with a radiochemical purity of greater than 99% and radiochemical yields of 42.7% ± 10.4% and 45.7% ± 6.5%, respectively, based on the total radioactivity of used radionuclides. I-IITM and At-AITM exhibited a maximum uptake of 4.66% ± 0.70 and 7.68% ± 0.71 percentage injected dose per gram (%ID/g) in the targeted melanomas, respectively, and were rapidly cleared from nontarget organs after intravenous injection. Both agents markedly inhibited melanoma growth compared with the controls (61.00% and 95.68%, respectively). In the melanoma model, considerably greater therapeutic efficacy with negligible toxicity was observed using At-AITM. The nontoxic radiopharmaceuticals I-IITM and At-AITM are useful high-precision TRT agents that can be used to target the oncoprotein mGluR1 for melanoma therapy.
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http://dx.doi.org/10.2967/jnumed.119.230946DOI Listing
February 2020

Directional assembly of a stapled α-helical peptide.

Chem Commun (Camb) 2019 Aug;55(70):10484-10487

State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.

The de novo design of stapled peptide-based self-assemblies attracts vast interest, yet still remains challenging. The development of an oxidation trigger for peptide stapling and subsequent self-assembly is described here. A self-assembling sequence, Fmoc-R(RCEX)2-NH2, transformed from a random coil to an α-helical structure upon disulphide bonding of the flanking cysteine residues positioning at the i/i + 4 locations. The stapling form of this peptide enforces a conformational restraint that affords the driving force for self-assembly into nanorod/nanovesicle structures. Moreover, these assembled materials can transport siRNA into cancer cells and immediately release the cargo in a reductive environment.
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http://dx.doi.org/10.1039/c9cc04591kDOI Listing
August 2019

BolA family member 2 enhances cell proliferation and predicts a poor prognosis in hepatocellular carcinoma with tumor hemorrhage.

J Cancer 2019 10;10(18):4293-4304. Epub 2019 Jul 10.

Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.

: BolA family member 2 (BOLA2) is a novel gene highly associated with human hepatocellular carcinoma (HCC) progression. Tumor hemorrhage (TH) acts as a poor marker for HCC patients and is a community affair in the tumor microenvironment. In the present study, we examined a possible association between BOLA2 levels and HCC patients with TH. : The mRNA and protein levels of BOLA2 were determined in two independent cohorts of HCC specimens by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) analysis, respectively. Survival curves and Cox regression models were used to evaluate the prognosis of HCC patients. The CRISPR/Cas9 system was used to knock out BOLA2 in HCC cells, and the functional role of BOLA2 in HCC cell proliferation and growth was examined. : BOLA2 mRNA expression is significantly higher in HCC tumour tissue than in nontumour tissue. Immunohistochemistry analysis of HCC tissues showed that BOLA2 protein was significantly correlated with TH, a more metastatic phenotype and worse HCC survival. The potential clinical relevance of BOLA2 expression and TH was validated by a Cox regression model. Furthermore, loss-of-function studies determined that BOLA2 plays critical roles in promoting iron overload, tumor growth and TH. Bioinformatics analysis from Gene Expression Profiling Interactive Analysis (GEPIA) revealed that BOLA2 is closely associated with the activation of p62-Keap1 signalling and ATG4B expression. These results were confirmed by immunohistochemistry analysis in HCC tissues. : Our results suggest that BOLA2 plays an important role in cancer biology and is an independent predictor of prognosis in HCC.
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http://dx.doi.org/10.7150/jca.31829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691716PMC
July 2019

Complete response of early stage hepatocellular carcinoma in a patient treated with combination therapy of camrelizumab (SHR-1210) and apatinib.

Dig Liver Dis 2019 10 7;51(10):1488-1490. Epub 2019 Aug 7.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2019.07.005DOI Listing
October 2019

A Comparative Genomic and Phylogenetic Analysis of the Origin and Evolution of the CCN Gene Family.

Biomed Res Int 2019 19;2019:8620878. Epub 2019 Jun 19.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

CCN gene family members have recently been identified as multifunctional regulators involved in diverse biological functions, especially in vascular and skeletal development. In the present study, a comparative genomic and phylogenetic analysis was performed to show the similarities and differences in structure and function of CCNs from different organisms and to reveal their potential evolutionary relationship. First, CCN homologs of metazoans from different species were identified. Then we made multiple sequence alignments, MEME analysis, and functional sites prediction, which show the highly conserved structural features among CCN metazoans. The phylogenetic tree was further established, and thus CCNs were found undergoing extensive lineage-specific duplication events and lineage-specific expansion during the evolutionary process. Besides, comparative analysis about the genomic organization and chromosomal CCN gene surrounding indicated a clear orthologous relationship among these species counterparts. At last, based on these research results above, a potential evolutionary scenario was generated to overview the origin and evolution of the CCN gene family.
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http://dx.doi.org/10.1155/2019/8620878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610741PMC
December 2019

Radiosynthesis and evaluation of a novel monoacylglycerol lipase radiotracer: 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[C]carboxylate.

Bioorg Med Chem 2019 08 29;27(16):3568-3573. Epub 2019 Jun 29.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[C]carboxylate ([C]6). Compound 6 exhibited high in vitro binding affinity (IC = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [C]6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [C]phosgene ([C]COCl), followed by a reaction with 3-(1-benzyl-1H-pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 ± 6.8% radiochemical yield (decay-corrected, n = 7) based on [C]CO and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [C]6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains.
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http://dx.doi.org/10.1016/j.bmc.2019.06.037DOI Listing
August 2019

The effectiveness of TDF versus ETV on incidence of HCC in CHB patients: a meta analysis.

BMC Cancer 2019 May 29;19(1):511. Epub 2019 May 29.

Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: It has been proved that nucleos(t) ide analogues (NAs) therapy could improve underlying liver disease and reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the difference of effectiveness in reducing HCC occurrence between tenofovir (TDF) and enticavir (ETV), two first-line NAs drugs, is still little known. This meta analysis aims to assess the efficacy in reducing incidence of HCC comparing tenofovir monotherapy with entecavir monotherapy among chronic hepatitis B (CHB) patients by analyzing their long-term clinical outcomes.

Methods: Databases including PubMed, Embase, Cochrane Central Register of Controlled Trial, and ISI Web of Science were fully investigated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For the included articles, two of the authors independently extracted and confirmed relevant data. Review Manager software (RevMan 5.3) was using for meta analysis.

Results: Seven articles with 3698 patients were finally included in this research, 1574 in tenofovir group and 2124 in entecavir group. For meta analysis, the incidence of HCC was significantly lower among the tenofovir group than entecavir group [rate ratio (95% CI) of 0.66 (0.49, 0.89), P = 0.008], while there was no statistical significance in incidence of death or transplantation [rate ratio (95% CI) of 0.78 (0.55, 1.13), P = 0.19], encephalopathy [risk ratio (95% CI) of 0.72 (0.45, 1.13), P = 0.15] or variceal bleeding [risk ratio (95% CI) of 0.71 (0.34, 1.50), P = 0.37] between the two groups.

Conclusion: There is a better effect of tenofovir in reducing HCC incidence than entecavir, which indicates tenofovir should be used more widely while treating chronic hepatitis B patients. However before applying, randomized controlled trial and large prospective cohort study should be performed in the future.
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http://dx.doi.org/10.1186/s12885-019-5735-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542001PMC
May 2019

Surface Coordination of Black Phosphorus with Modified Cisplatin.

Bioconjug Chem 2019 06 22;30(6):1658-1664. Epub 2019 May 22.

State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology , Peking University Shenzhen Graduate School , Shenzhen 518055 , China.

Black phosphorus (BP) is a two-dimensional (2D) nanomaterial with high charge-carrier mobility, a tunable direct bandgap, and a unique in-plane anisotropic structure; however, the easiness of BP oxidation into P O species in ambient conditions largely limits its applications. In this study, modified cisplatin-Pt-NO [Pt(NH)(NO)] is used for surface coordination with BP nanosheets to generate Pt@BP, which maintains the surface morphology and properties of BP nanosheets for more than 24 h in ambient conditions. In addition, Pt@BP interacts with DNA both in vitro and in cell. Pt@BP shows a good cellular uptake rate and significantly increases the drug sensitivity of cisplatin-resistant cancer cell lines (A2780 and HepG2) compared with unmodified cisplatin. Our study is the first attempt to stabilize bare BP with cationic cisplatin species, and the generated Pt@BP could be used for potential synergistic photothermal/chemotherapy of cisplatin-resistant cancer.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00128DOI Listing
June 2019